Protocol CV185074: evaluation of multiple dose pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban in healthy subjects

The drug to be given, apixaban, is a so-called Factor Xa inhibitor. Factor Xa
is one of the coagulation factors that play a key role in blood clotting after
an injury or surgery. Apixaban is a new, investigational compound that may
eventually be used for the treatment and prevention of venous thromboembolism
(VTE) which may occur after knee or hip replacement surgery. Venous
thromboembolism (VTE) is the formation of a blood clot in one of the deep veins
within the body, such as in the leg or pelvis. This kind of thrombosis can
occur after surgery and may cause redness, pain and swelling as well as
pulmonary embolism and stroke. Apixaban is an antithrombotic drug which reduces
thrombus or blood clot formation by limiting the ability of the platelets to
clot.

Primary:
- to assess the multiple-dose pharmacokinetics of apixaban and rivaroxaban
- to compare plasma concentration peak to trough ratio (Cmax/Cmin) of
rivaroxaban to apixaban

Secondary:
- to assess the multiple dose pharmacodynamics (anti-Factor Xa activity) of
apixaban and rivaroxaban
- to assess the safety and tolerability of apixaban

Exploratory:
- to explore the metabolites of rivaroxaban in plasma in healthy subjects

Design:
An open-label, randomized, crossover study.

Procedures and assessments
Screening and follow-up:
Clinical laboratory, pregnancy test (females only), vital signs (including body
temperature, respiratory rate) full physical examination, weight, 12-lead ECG.

Observation period:
16 continues days, divided in two periods.

Blood sampling:
- for pharmacokinetics and pharmacodynamics of Rivaroxaban: up to Day 4
- for pharmacokinetics and pharmacodynamics of Apixaban: up to Day 4
- for biotransformation sample: 4 and 24 h post-dose on Day 4 during Treatment A

Urine sampling:
N.A.

Faeces sampling:
N.A.

Safety assessments:
Adverse events: throughout the study; physical examination: on Day 8 (Day -1,
Period 2) clinical laboratory: once on Day 8 (Day -1, Period 2) and once on Day
8 (Day -1, Period 2); vital signs (including oral temperature): pre-dose and
once on Day 8 (Day -1, Period 2) and once on Day 8 (Day -1, Period 2); 12-lead
ECG: pre-dose and once on Day 1 (Part 1) and pre-dose (Day -1, Period 2);
pregnancy test (females only) on Day 8 (Day -1 Period 2).

Bioanalysis:
- analysis of plasma rivaroxaban and apixaban samples using a validated method
at PRA
- analyse of FxA activity using a validated method by PRA

Study Medication
Active substance:
Rivaroxaban and Apixaban.

Procedure:
Pain, light bleeding, heamatoma, possibly an infection.